This is a revised New Investigator-initiated R01 application designed to understand the neurobiological mechanisms underlying methamphetamine addiction, as well as the effects of pharmacological treatments aimed at curbing substance abuse. Specifically, the role of nicotinic acetylcholine receptors (nAChRs) in the abuse-related effects of methamphetamine is poorly understood. For example, indirect nAChR agonists, or antagonists in preclinical and clinical studies have reported decreases in the abuse-related effects of methamphetamine. This application proposes to address this critical barrier to scientific progress regarding the role of nAChR in the abuse-related effects of methamphetamine. Our working hypothesis is that the abuse-related effects of methamphetamine are mediated through combined dopamine (DA) and acetylcholine (ACh) release. Accordingly, we propose the following Specific Aims using a within-subjects design in rhesus monkeys. Aim#1 will determine the effects of DA and nAChR agonists and antagonists on the discriminative stimulus effects of methamphetamine. Aim#2 will determine the effects of maintenance on an indirect DA agonist or DA antagonist nAChR antagonist on the reinforcing effects of methamphetamine. PUBLIC HEALTH RELEVANCE: Methamphetamine abuse is a major public health problem with no Food and Drug Administration-approved pharmacotherapies or effective treatment strategies. The clandestine manufacture of methamphetamine from over-the-counter cold remedies (pseudoephedrine) also poses a public health risk because the ingredients are highly flammable and explosive. This application proposes preclinical studies to determine the pharmacological mechanisms of methamphetamine abuse towards the development of pharmacotherapies. Our public health goal is to promote the translation of preclinical results to positive clinical outcomes in treating methamphetamine abuse.